Cancer immunotherapy: Current challenges: The promise of cancer immunotherapy has now been rapidly realized, in studies largely conducted just over the past decade. Despite tremendous advances, challenges remain, particularly with respect to treatment of immunologically “cold” tumors such as pediatric sarcomas and malignant gliomas. Solid tumors in general represent a significant barrier to adoptive T cell transfer, and checkpoint antibody therapeutics are generally relatively ineffective in low T cell infiltrated cancers. Personalized cancer vaccines are difficult currently to produce quickly, and induction of effective immunity is not always possible.

Role of the TME in regulating tumor immunity: The immune suppressive tumor microenvironment (TME) is a major impediment to effective cancer immunotherapy. Particular TME barriers include immune suppressive stromal cells (e.g., tumor macrophages, cancer fibroblasts, Tregs) and physical stromal barriers such as fibrotic responses and extracellular matrix. Overcoming these local tumor barriers represents a fundamental challenge to successful cancer immunotherapy.

Modifying the TME: One approach to reduce immune suppression within the TME is to deplete or functionally alter immune suppressive cell populations. We have evaluated several different strategies. In one approach, macrophages can be depleted directly (e.g., liposomal clodronate) or activated locally (e.g., by injection of TLR3 or 9 agonists). A third strategy, which we have been investigating in both osteosarcoma and glioma trials, is to induce sustained blockade of recruitment of inflammatory monocytes to the tumor, which over time leads to macrophage depletion. To accomplish this clinically in dogs, we have repurposed the angiotensin receptor blocker (losartan) as a novel CCR2 antagonist and monocyte migration inhibitor, together with toceranib, which leads to Treg depletion. The two drugs in combination have been shown to induce tumor regression in metastatic osteosarcoma and to enhance vaccine effectiveness in glioma. Additional studies are underway to more fully define the mechanisms of action of these drugs in canine cancer.